1. Field of the Invention
The invention relates to vaginal suppositories and methods of intra-vaginal delivery of drugs. More particularly, it concerns treatment of progesterone deficiency conditions with a vaginal tablet or insert. 2. General Discussion of the Background
The major biologic functions of progesterone are to prepare the uterine endometrium for fertilization and implantation and to support pregnancy. In addition, progesterone has the ability to inhibit the rhythmic contractions attributed to the natural spontaneous contractile properties of the myometrial layer of the uterus.
The secretion of progesterone by the ovary begins just prior to ovulation from the follicle that is destined to release an ovum. After ovulation, the follicle becomes the corpus luteum, which is the primary source of endogenous progesterone. Progesterone converts estrogen primed proliferating endometrial cells of the uterus into mature secretory cells. During this conversion, mature endometrial cells and glands are produced, along with blood vessels and carbohydrates necessary to support a fertilized ovum if conception occurs. If conception does not occur, the corpus luteum regresses and progesterone production decreases. This leads to necrosis of the endometrial cells and glands with sloughing of the epithelial layer of the endometrium.
During normal formation of the uterine endometrium within a menstrual cycle, estrogens are necessary for cellular proliferation and progesterone is needed for maturation and secretory gland formation. An estrogen stimulated proliferative endometrium must be present for progesterone to induce a secretory endometrium. If an estrogen primed proliferative endometrium does not proceed to a secretory phase, it usually is because of anovulation and insufficient progesterone production. If insufficient progesterone exists, then minimal to no secretory epithelium is formed and menstrual bleeding is incomplete or does not occur.
The natural secretion of progesterone is 1-2 mg/day during the follicular phase of the menstrual cycle. During the luteal phase, the rate of secretion increases to 10-20 mg/day. The reference serum levels for progesterone are 0.1-1.5 ng/ml for the follicular phase and 2.5-28.1 ng/ml for the luteal phase. For mid-luteal phase, values of 5.7-28.1 ng/ml are reported. In the later stages of pregnancy, the secretion is several hundred mg/day of progesterone.
Inactivation of progesterone takes place largely in the liver. While most of the metabolites of progesterone are unidentified, one of the major urinary products is the glucuronide of pregnane-3a,20a-diol. About 50 to 60% of administered radiolabeled progesterone appears in the urine and about 10% in feces. Pregnanediol in urine accounts for 12 to 15% of the progesterone metabolized.
The rate of turnover of endogenous progesterone is rapid, the plasma half-life being a few minutes. The half-life of progesterone after intravenous injections has two phases. The first half-life is 5-6 minutes and the second is 42-45 minutes. A small amount of progesterone is stored in body fat, but this is generally regarded as quantitatively unimportant.
In the absence of organic pathology, such as submucous fibroids, uterine cancer, or infections, the infrequency or absence of the menstrual bleed usually results from abnormalities in the production of estrogen and/or progesterone. Such conditions are usually referred to as amenorrhea or functional uterine bleeding. It is usually impossible to reduce the issue of the etiology of abnormal menstrual function, to a single factor except in disease states such as pituitary tumors. The following can alter the production of progesterone and result in progesterone deficiency conditions:
1. Ovarian Failure. Hypergonadotrophic hypogonadism, or the inability of the ovary to respond to any gonadotrophic stimulation, is usually due to the absence of follicular tissue on a genetic basis.
2. Central Failure. Hypogonadotrophic hypogonadism, involves hypothalamic or pituitary suppression expressed in low serum gonadotrophins.
3. Anovulatory Dysfunction. The- patient who has asynchronous gonadotrophin and estrogen productions and does not ovulate can present with a variety of clinical manifestations. The associated clinical signs and symptoms depend upon the level of gonadal function preserved. Lack of or infrequent menstrual bleeds is a common finding.
By definition, amenorrhea is the failure to menstruate. It is a symptom rather than a disease and has many possible causes. Amenorrhea can result from disturbed reactions anywhere in the hypothalamic-pituitary-ovarian-uterine axis, with or without an associated organic lesion. Any patient who has a history of previously menstruating, but who now has absence of menstrual bleeding with a negative pregnancy test, is usually evaluated for the clinical problem of amenorrhea.
The normal ovulatory function of the menstrual system relies on a dynamic coordination of complex actions. Thus, a minor deficiency in the estradiol signal may be associated with a subnormal central response and an impaired or inappropriate degree of follicular growth and function. Dysfunction is sustained by abnormal fluctuations in the internal feedback mechanisms within the hypothalamic - pituitary - ovarian systems, and functional uterine bleeding may become a persistent problem. This usually results in erratic menstrual bleeding patterns.
Thus, failure to menstruate or infrequent or incomplete menstrual bleeding, in the absence of pathology, is usually associated with insufficient quantities of estrogens to initiate the proliferative phase of the endometrium and/or the absence of progesterone to convert estrogen-primed endometrium into a mature decidual epithelium with secretory glands and cells. The latter transformation to a mature epithelium must occur prior to any type of sloughing. The sloughing and concomitant bleeding is recognized as menstruation. Absence of endometrial maturation under the influence of progesterone results in amenorrhea.
The commonly employed routes of progesterone administration have limitations (Steege et al., Fertil. Steril. 46:727-729 (1986)). Absorption of orally administered micronized progesterone is influenced by stomach contents, first-pass liver metabolism and other unknown factors, resulting in significant but highly variable serum levels, thus reducing the therapeutic usefulness of oral progesterone. These problems with oral administration are sometimes avoided by using synthetic progestins. The absorption of progesterone by the rectal route is influenced by the first-pass effects of the liver and absorption is highly variable, thus limiting that pathway of administration. Parenteral administration requires deep intramuscular injections which are often very painful and irritating at the site of injection. Although parenteral administration permits the use of natural hormones rather than progestins, variations in peak plasma levels require dosages of 5 to 10 mg daily for 6 to 8 days.
Since progesterone is absorbed via the vaginal epithelium and it is not commercially available as a vaginal preparation, pharmacists routinely compound fatty acid and cocoa butter progesterone suppositories for patient use. Unfortunately, these suppositories are expelled from the vagina by coughing or sneezing. Moreover, the suppository quickly melts, which allows it to leak out of the vagina and soil a patient's clothing. The rapid dissolution of these prior vaginal suppositories has also greatly reduced.. their bioavailability.
A contraceptive vaginal tablet is disclosed in U.S. Pat. No. 4,565,694. It contains boric acid, tartaric acid, vitamin K.sub.3, a lubricant and sufficient disintegrants to disintegrate quickly after vaginal insertion. Quick dissolution of the tablet allows dispersal of its spermicidal contents, but greatly reduces the bioavailability of any drug contained in the tablet.
U.S. Pat. No. 4,585,782 discloses a vaginal tablet for rapidly dispersing an antimycotic composition. The composition is formulated to reduce the pH of the formulation to about 3-6. This low pH greatly increases the rate of release of the entire composition. Unfortunately, sustained release of a drug is not possible with such a tablet. Bioavailability of the drug is therefore reduced.
It is therefore an object of this invention to provide a vaginal tablet having prolonged bioavailability.
It is another object of this invention to provide such a tablet which is suitable for treating progesterone deficiency conditions.
Yet another object of the invention is to provide a vaginal suppository in which the pharmaceutically active component is retained within the vagina.